Inhibition of Endoplasmic Reticulum Stress–Induced Apoptosis of Melanoma Cells by the ARC Protein

Chen, Li Hua; Jiang, Chen Chen; Watts, Ralph N.; Thorne, Rick F.; Kiejda, Kelly A.; Zhang, Xu Dong; Hersey, Peter

doi:10.1158/0008-5472.can-07-5056

Cited by 40 publications

(38 citation statements)

References 40 publications

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“…A number of BH3-only proteins, including PUMA, Noxa, Bim, and BIK, have been shown to be upregulated/activated (8)(9)(10)(11)(12)(13), whereas Bcl-2 and Mcl-1 have been reported to be down-regulated (14,15), thus contributing to induction of apoptosis by ER stress. In addition, various other mechanisms have been shown to play roles in initiating apoptotic signaling by ER stress, such as activation of caspase-8, caspase-2, and caspase-12 in murine systems and its counterpart caspase-4 in human cells (5,6,(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

“…Most cultured human melanoma cell lines are not sensitive to ER stress-induced apoptosis (17,18). Whereas the mitogen-activated protein/extracellular signal-regulated kinase (MEK)/ERK signaling pathway is important for inhibiting ER stress-induced caspase-4 activation (18), the apoptosis repressor with caspase recruitment domain (ARC) protein is critical in blocking activation of casapse-8 in melanoma cells subjected to ER stress (17).…”

Section: Introductionmentioning

confidence: 99%

“…Whereas the mitogen-activated protein/extracellular signal-regulated kinase (MEK)/ERK signaling pathway is important for inhibiting ER stress-induced caspase-4 activation (18), the apoptosis repressor with caspase recruitment domain (ARC) protein is critical in blocking activation of casapse-8 in melanoma cells subjected to ER stress (17). It seems that ER stress can potentially activate multiple apoptosis signaling pathways, but they are apparently inhibited, conceivably also by various mechanisms such as activation of MEK and ARC, in melanoma cells.…”

Section: Introductionmentioning

confidence: 99%

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Up-regulation of Mcl-1 Is Critical for Survival of Human Melanoma Cells upon Endoplasmic Reticulum Stress

et al. 2008

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We have previously shown that most melanoma cell lines are insensitive to endoplasmic reticulum (ER) stress-induced apoptosis, and this involves activation of the mitogen-activated protein/extracellular signal-regulated kinase (MEK)/ERK signaling pathway and expression of the apoptosis repressor with caspase recruitment domain (ARC) protein in the cells. In the present study, we show that up-regulation of the antiapoptotic Bcl-2 family member Mcl-1 is another mechanism critical for protection of melanoma cells against ER stress-induced apoptosis. Inhibition of Mcl-1 by small interference RNA (siRNA) rendered melanoma cells sensitive to apoptosis induced by the ER stress inducers thapsigargin and tunicamycin, but this sensitization was partially reversed by siRNA knockdown of PUMA or Noxa, as shown in Mcl-1-deficient melanoma cells. Both PUMA and Noxa were increased by ER stress through transcriptional up-regulation, but only up-regulation of Noxa was dependent on p53, whereas up-regulation of PUMA seemed to be mediated by a p53-independent mechanism(s). Upregulation of Mcl-1 was also due to increased transcription that involved the IRE1A and activating transcription factor 6 signaling pathways of the unfolded protein response. In addition, activation of the MEK/ERK signaling pathway seemed to be necessary for optimal up-regulation of Mcl-1. Taken together, these results reveal the mechanisms of resistance of melanoma cells to apoptosis induction mediated by BH3-only proteins upon ER stress, and identify Mcl-1 as a target for the treatment of melanoma in combination with therapeutics that induce ER stress. [Cancer Res 2008;68(16):6708-17]

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Up-regulation of Mcl-1 Is Critical for Survival of Human Melanoma Cells upon Endoplasmic Reticulum Stress

et al. 2008

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“…The proliferation of Me4405, Me10538 and Me2211M2 was inhibited by TRAIL in a dose-dependent manner, while Me1007 cells were resistant to this drug (Supplementary Figure S1) in keeping with the their low expression of caspase-8 (Zhang et al, 2001), a key mediator of the extrinsic apoptosis pathway (Chen et al, 2008). TRAIL-induced apoptosis was accompanied by cleavage of PARP, strongly detectable in all the lines except Me1007 (Figure 1), and by activation of caspase-8 yielding the cleaved p41 and 43 forms.…”

Section: Trail Sensitivity In Melanoma Cell Linesmentioning

confidence: 91%

“…Two inducers of endoplasmic reticulum (ER) stress, Thapsigargin and Tunicamycin, have been suggested to sensitise Me1007 to TRAIL by upregulation of TRAIL-R2 Jiang et al, 2007) and caspase-8 (Chen et al, 2008). As Bortezomib can also cause ER stress (Boccadoro et al, 2005), we checked whether it upregulated caspase-8 in Me1007, but no evidence for this was observed, even in response to elevated doses of Bortezomib ( Figure 3B).…”

Section: Bortezomib Sensitises Melanoma Cells Without Affecting Caspamentioning

confidence: 95%

Novel SMAC-mimetics synergistically stimulate melanoma cell death in combination with TRAIL and Bortezomib

et al. 2010

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BACKGROUND: XIAP (X-linked inhibitor of apoptosis protein) is an anti-apoptotic protein exerting its activity by binding and suppressing caspases. As XIAP is overexpressed in several tumours, in which it apparently contributes to chemoresistance, and because its activity in vivo is antagonised by second mitochondria-derived activator of caspase (SMAC)/direct inhibitor of apoptosisbinding protein with low pI, small molecules mimicking SMAC (so called SMAC-mimetics) can potentially overcome tumour resistance by promoting apoptosis. METHODS: Three homodimeric compounds were synthesised tethering a monomeric SMAC-mimetic with different linkers and their affinity binding for the baculoviral inhibitor repeats domains of XIAP measured by fluorescent polarisation assay. The apoptotic activity of these molecules, alone or in combination with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and/or Bortezomib, was tested in melanoma cell lines by MTT viability assays and western blot analysis of activated caspases. RESULTS: We show that in melanoma cell lines, which are typically resistant to chemotherapeutic agents, XIAP knock-down sensitises cells to TRAIL treatment in vitro, also favouring the accumulation of cleaved caspase-8. We also describe a new series of 4-substituted azabicyclo[5.3.0]alkane monomeric and dimeric SMAC-mimetics that target various members of the IAP family and powerfully synergise at submicromolar concentrations with TRAIL in inducing cell death. Finally, we show that the simultaneous administration of newly developed SMAC-mimetics with Bortezomib potently triggers apoptosis in a melanoma cell line resistant to the combined effect of SMAC-mimetics and TRAIL. CONCLUSION: Hence, the newly developed SMAC-mimetics effectively synergise with TRAIL and Bortezomib in inducing cell death. These findings warrant further preclinical studies in vivo to verify the anticancer effectiveness of the combination of these agents.

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Inhibition of microRNA‐327 ameliorates ischemia/reperfusion injury‐induced cardiomyocytes apoptosis through targeting apoptosis repressor with caspase recruitment domain

Yang

Zhang

et al. 2019

Journal Cellular Physiology

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Apoptosis is the major cause of cardiomyocyte death in myocardial ischemia/reperfusion injury (MI/RI). Increasing evidence suggests that microRNAs (miRNAs) can contribute to the regulation of cardiomyocytes apoptosis by posttranscriptional modulation of gene expression networks. However, the effects of miR-327 in regulating MI/RI-induced cardiomyocytes apoptosis have not been extensively investigated. This study was performed to test whether miR-327 participate in cardiomyocytes apoptosis both in vitro and in vivo, and reveal the potential molecular mechanism of miR-327 regulated MI/RI through targeting apoptosis repressor with caspase recruitment domain (ARC).Sprague-Dawley (SD) rats were subjected to MI/RI by left anterior descending coronary artery occlusion for 30 min and reperfusion for 3 hr. H9c2 cells were exposed to hypoxia for 4 hr and reoxygenation for 12 hr to mimic I/R injury. miRNA-327 recombinant adenovirus vectors were transfected into H9c2 cells for 48 hr and rats for 72 hr before H/R and MI/RI treatment, respectively. The apoptosis rate, downstream molecules of apoptotic pathway, and the target reaction between miRNA-327 and ARC were evaluated.Our results showed that miR-327 was upregulated and ARC was downregulated in the myocardial tissues of MI/RI rats and in H9c2 cells with H/R treatment. Inhibition of miR-327 decreased the expression levels of proapoptotic proteins Fas, FasL, caspase-8, Bax, cleaved caspase-9, cleaved caspase-3, and the release of cytochrome-C, as well as increasing the expression levels of antiapoptotic protein Bcl-2 via negative regulation of ARC both in vivo or vitro. In contrast, overexpression miR-327 showed the reverse effect.Moreover, the results of luciferase reporter assay indicated miR-327 targets ARC directly at the posttranscriptional level. Taken together, inhibition of miR-327 could attenuate cardiomyocyte apoptosis and alleviate I/R-induced myocardial injury via targeting ARC, which offers a new therapeutic strategy for MI/RI.

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Inhibition of Endoplasmic Reticulum Stress–Induced Apoptosis of Melanoma Cells by the ARC Protein

Cited by 40 publications

References 40 publications

Up-regulation of Mcl-1 Is Critical for Survival of Human Melanoma Cells upon Endoplasmic Reticulum Stress

Up-regulation of Mcl-1 Is Critical for Survival of Human Melanoma Cells upon Endoplasmic Reticulum Stress

Novel SMAC-mimetics synergistically stimulate melanoma cell death in combination with TRAIL and Bortezomib

Inhibition of microRNA‐327 ameliorates ischemia/reperfusion injury‐induced cardiomyocytes apoptosis through targeting apoptosis repressor with caspase recruitment domain

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